Accumulating evidence suggests that proinflammatory cytokines play an important role in white matter injury in preterm infants, a condition in which oligodendrocyte (OL) progenitor cells are preferentially injured. We investigated the role of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and its death (TRAIL-R1, TRAIL-R2) and decoy (TRAIL-R3, TRAIL-R4) receptors in periventricular white matter injury (PWMI). We hypothesized that the maturation-dependent vulnerability of OLs to TRAIL is due to the differential TRAIL receptor expression. We previously investigated TRAIL/TRAIL receptor expression levels in rat OLs in vivo in the context of PWMI. We found that during different developmental stages, human OLs differentially express TRAIL receptors; and there is a progressive loss of sensitivity to TRAIL as OLs proceed through the maturation process. Our results show that both TRAIL-R1 and -R2 are highly expressed on human OL progenitors and pre-OLs, while TRAIL-R3 and TRAIL-R4 are mainly expressed on immature and mature human OLs. Our results suggest that TRAIL-R1 and TRAIL-R2 might mediate the death signal in human OL precursor cells and pre-OLs.